GeneBe

ESRRB

protein-coding

estrogen related receptor beta, the group of Estrogen related receptors

Gene summary

This gene encodes a protein with similarity to the estrogen receptor. Its function is unknown; however, a similar protein in mouse plays an essential role in placental development. [provided by RefSeq, Jul 2008]

Previous symbols:
  • ESRL2
  • DFNB35

MANE transcript

NM_001379180.1

Inheritance

AR

ClinVar variants

P:28U:106B:51

Top phenotype

Deafness, autosomal recessive 35

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr14:76,310,712-76,501,837

External References & Databases

Ensembl (ENSG00000119715)NCBI Gene (2103)OMIM (602167)HGNC:3473GenCCUniProt (O95718)AlphaFoldClinVar (ESRRB)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~191.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012060

Submitter: Ambry Genetics

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012060

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 35DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012060

Submitter: G2P

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between ESRRB and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/1/2017. Variants in ESRRB were first associated with this disease in humans as early as 2008 (Collin et al.). At least 9 variants (missense, in-frame del, frameshift, and a multiexon deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 9 probands in 4 publications as well as unpublished data (18179891, 21802533, 22567352, 22951369, Partners LMM unpublished data). Variants in this gene segregated with disease in 7 additional family members. This gene-disease association is supported by a mouse model and relevant expression studies (Chen et al. 2007, Collin et al. 2008). In summary, ESRRB is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 4/24/2018​.

autosomal recessive nonsyndromic hearing loss 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012060

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 35AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 12529709; 18179891; 26805784Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ESRRB variants in ClinVar

9 Conditions Cataloged
not providedTotal: 152
not specifiedTotal: 85
Autosomal recessive nonsyndromic hearing loss 35Total: 46
Rare genetic deafnessTotal: 5
ESRRB-related disorderTotal: 5
Hearing impairmentTotal: 2
Hearing loss, autosomal recessiveTotal: 1
Premature ovarian insufficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001379180.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
6
clinvar
42
clinvar
 48
missense
5
clinvar
6
clinvar
98
clinvar
8
clinvar
1
clinvar
 118
nonsense
3
clinvar
4
clinvar
 7
start loss
0
frameshift
3
clinvar
4
clinvar
1
clinvar
 8
splice donor/acceptor (+/-2bp)
3
clinvar
1
clinvar
 4
Total1117106501185

Highest pathogenic variant AF is 0.0000340914

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001379180.1RefSeqNP_001366109.17MANE Select
ENST00000644823.1EnsemblENSP00000493776.17MANE Select
NM_001411038.1RefSeqNP_001397967.17Standard
NM_004452.4RefSeqNP_004443.38Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
  • NHR
  • Nuclear Receptors
  • Wnt Signaling Pathway and Pluripotency
  • Gene expression (Transcription)

Biological Process

  • embryonic placenta development
  • regulation of transcription, DNA-templated
  • transcription initiation from RNA polymerase II promoter
  • stem cell division
  • stem cell population maintenance

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • RNA polymerase II distal enhancer sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • RNA polymerase II complex binding
  • enhancer sequence-specific DNA binding

Cellular Component

  • condensed chromosome
  • nucleus
  • nucleoplasm
  • cytoplasm
  • integrator complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000380887
Coding exons
8
Length
191222
Individuals with no LoFs
125722
Homozygous LoFs
0
Heterozygous LoFs
26
Defined
125748
p
0.000103
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.562293060.7490.00002013270
Missense (PolyPhen)61109.010.559561167
Synonymous0.6281291380.9320.00001061022
Loss of Function3.26622.80.2630.00000123250

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000490.00049rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000470.000044rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Isoform 3: Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5'TCAAGGTCA-3' localized on promoter and enhancer of targets genes regulating their expression or their transcription activity (PubMed:17920186, PubMed:19755138). Plays a role, in a LIF-independent manner, in maintainance of self-renewal and pluripotency of embryonic and trophoblast stem cells through different signaling pathways including FGF signaling pathway and Wnt signaling pathways. Upon FGF signaling pathway activation, interacts with KDM1A by directly binding to enhancer site of ELF5 and EOMES and activating their transcription leading to self-renewal of trophoblast stem cells. Also regulates expression of multiple rod-specific genes and is required for survival of this cell type (By similarity). Plays a role as transcription factor activator of GATA6, NR0B1, POU5F1 and PERM1 (PubMed:23836911). Plays a role as transcription factor repressor of NFE2L2 transcriptional activity and ESR1 transcriptional activity (PubMed:17920186, PubMed:19755138). During mitosis remains bound to a subset of interphase target genes, including pluripotency regulators, through the canonical ESRRB recognition (ERRE) sequence, leading to their transcriptional activation in early G1 phase. Can coassemble on structured DNA elements with other transcription factors like SOX2, POU5F1, KDM1A and NCOA3 to trigger ESRRB-dependent gene activation. This mechanism, in the case of SOX2 corecruitment prevents the embryonic stem cells (ESCs) to epiblast stem cells (EpiSC) transition through positive regulation of NR0B1 that inhibits the EpiSC transcriptional program. Also plays a role inner ear development by controlling expression of ion channels and transporters and in early placentation (By similarity). {ECO:0000250|UniProtKB:Q61539, ECO:0000269|PubMed:17920186, ECO:0000269|PubMed:19755138, ECO:0000269|PubMed:23836911}.;
Disease
DISEASE: Deafness, autosomal recessive, 35 (DFNB35) [MIM:608565]: A form of non-syndromic deafness characterized by non-progressive, prelingual hearing loss. {ECO:0000269|PubMed:18179891}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.203

Intolerance Scores

LoFtool
0.193
RVIS EVS
0.18
RVIS percentile EVS
66.07

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.966

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.